1. Field of the Invention
The present invention relates to 2-(1-isopropoxycarbonyloxy-2-methylpropyl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine, which is in amorphous form and possesses improved dissolution and absorption, and a pharmaceutical composition comprising the same.
2. Background Art
2-(1-Isopropoxycarbonyloxy-2-methylpropyl)-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine (hereinafter referred to as “compound A”) is a compound, represented by the following chemical structural formula, as disclosed in WO 99/16770 (Japanese Patent No. 3188482 and U.S. Pat. No. 6,372,735) (the disclosure of each of these publications is incorporated herein by reference).

Upon oral administration, this compound exhibits a mast cell membrane stabilizing action and an inhibitory activity against allergic inflammation and thus is expected to be used clinically as oral antiallergic agents. Since, however, compound A, when used in a crystalline form (hereinafter referred to as “crystalline compound A”), is poorly soluble, the compound contained in a formulation is hardly absorbed within the digestive tract and is less likely to be absorbed in a body. Therefore, improving solubility and bioavailability of crystalline compound A is required for the design and production of oral preparations.
The present inventors have attempted various methods with a view to improving the dissolvability of crystalline compound A. As a result, it was found that the dissolution of crystalline compound A with the aid of an acidic or basic additive is difficult due to the absence of a functional group, which is dissociated or protonated in a pharmaceutically acceptable pH range, in the structure of compound A. Further, even after inclusion compounds, such as cyclodextrins, or various surfactants, polymeric compounds or the like are added, crystalline compound A could not be substantially solubilized without difficulties. Furthermore, the solubility of crystalline compound A in glycerin, propylene glycol, Macrogol 400 and the like was not on such a level that can make crystalline compound A pharmaceutically usable. In addition, an experiment in which a pulverized crystal of crystalline compound A is prepared according to the description of Japanese Patent Laid-Open No. 185013/1987 disclosing a drug, which has been rendered easily absorbable by pulverizing was carried out. The treated drug is orally administered to experimental animals such as dogs. As a result, it was found that an improvement in absorption of preparations using crystalline compound A is not more than expected.
A technique known for improving the dissolution of the hardly soluble crystalline compound is to convert the crystalline compound to an amorphous compound (for example, Yu L., Advanced Drug Delivery Reviews, Vol. 48, p. 29, 2001). Specific examples thereof include heat melting, rapid crystallization by the addition of a hardly soluble solvent, lyophilization, spray drying, preparation of solid dispersion, mechanochemical conversion (such as commutation), and dehydration from crystalline hydrate. Most of common techniques for rendering drugs amorphous, however, could not be applied to crystalline compound A due to the occurrence of unfavorable phenomena including that crystalline compound A is decomposed upon heat melting due to closeness of the melting point to the decomposition point; precipitation as a crystal is observed even by the rapid crystallization method; there is no proper solvent for lyophilization; crystalline compound A is not heat melted even in a thermal plastic substance and, even when dissolved in a solvent together with various additives, causes crystallization during the removal of the solvent by distillation under the reduced pressure (that is, a solid dispersion cannot be prepared by the melting method and the solvent distilling-off method); pulverization or extruder treatment does not render crystalline compound A amorphous or results in the formation of a decomposition product; and any hydrate is not formed.